Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy

Yang Liu, Joseph M. Eckenrode, Yinan Zhang, Jianjun Zhang, Reiya C. Hayden, Annet Kyomuhangi, Larissa V. Ponomareva, Zheng Cui, Jürgen Rohr, Oleg V. Tsodikov, Steven G. Van Lanen, Khaled A. Shaaban, Markos Leggas, Jon S. Thorson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Mithramycin A (MTM) inhibits the oncogenic transcription factor EWS-FLI1 in Ewing sarcoma, but poor pharmacokinetics (PK) and toxicity limit its clinical use. To address this limitation, we report an efficient MTM 2′-oxime (MTMox) conjugation strategy for rapid MTM diversification. Comparative cytotoxicity assays of 41 MTMox analogues using E-twenty-six (ETS) fusion-dependent and ETS fusion-independent cancer cell lines revealed improved ETS fusion-independent/dependent selectivity indices for select 2′-conjugated analogues as compared to MTM. Luciferase-based reporter assays demonstrated target engagement at low nM concentrations, and molecular assays revealed that analogues inhibit the transcriptional activity of EWS-FLI1. These in vitro screens identified MTMox32E (a Phe-Trp dipeptide-based 2′-conjugate) for in vivo testing. Relative to MTM, MTMox32E displayed an 11-fold increase in plasma exposure and improved efficacy in an Ewing sarcoma xenograft. Importantly, these studies are the first to point to simple C3 aliphatic side-chain modification of MTM as an effective strategy to improve PK.

Original languageEnglish
Pages (from-to)14067-14086
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number22
StatePublished - Nov 25 2020

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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